Time rescaling reproduces EEG behavior during transition from propofol anesthesia-induced unconsciousness to consciousness.

General anesthesia (GA) is a reversible manipulation of consciousness whose mechanism is mysterious at the level of neural networks leaving space for several competing hypotheses. We recorded electrocorticography (ECoG) signals in patients who underwent intracranial monitoring during awake surgery for the treatment of cerebral tumors in functional areas of the brain. Therefore, we recorded the transition from unconsciousness to consciousness directly on the brain surface. Using frequency resolved interferometry; we studied the intermediate ECoG frequencies (4-40 Hz). In the theoretical study, we used a computational Jansen and Rit neuron model to simulate recovery of consciousness (ROC). During ROC, we found that f increased by a factor equal to 1.62 ± 0.09, and δf varied by the same factor (1.61 ± 0.09) suggesting the existence of a scaling factor. We accelerated the time course of an unconscious EEG trace by an approximate factor 1.6 and we showed that the resulting EEG trace match the conscious state. Using the theoretical model, we successfully reproduced this behavior. We show that the recovery of consciousness corresponds to a transition in the frequency (f, δf) space, which is exactly reproduced by a simple time rescaling. These findings may perhaps be applied to other altered consciousness states.

EZH2 alterations in follicular lymphoma: biological and clinical correlations.

The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n=46, gain n=23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36-0.93, P=0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.

[Economic assessment of pulsed dose-rate (PDR) brachytherapy with optimized dose distribution for cervix carcinoma]. / Evaluation économique de la curiethérapie de débit pulsé gynécologique (PDR) avec optimisation de la dose pour les cancers du col utérin.

PURPOSE: Our study aims at evaluating the cost of pulsed dose-rate (PDR) brachytherapy with optimized dose distribution versus traditional treatments (iridium wires, cesium, non-optimized PDR). Issues surrounding reimbursement were also explored. MATERIALS AND METHODS: This prospective, multicentre, non-randomised study conducted in the framework of a project entitled "Support Program for Costly Diagnostic and Therapeutic Innovations" involved 21 hospitals. Patients with cervix carcinoma received either classical brachytherapy or the innovation. The direct medical costs of staff and equipment, as well as the costs of radioactive sources, consumables and building renovation were evaluated from a hospital point of view using a microcosting approach. Subsequent costs per brachytherapy were compared between the four strategies. RESULTS: The economic study included 463 patients over two years. The main resources categories associated with PDR brachytherapy (whether optimized or not) were radioactive sources (1053euro) and source projectors (735euro). Optimized PDR induced higher cost of imagery and dosimetry (respectively 130euro and 367euro) than non-optimized PDR (47euro and 75euro). Extra costs of innovation over the less costly strategy (iridium wires) reached more than 2100euro per treatment, but could be reduced by half in the hypothesis of 40 patients treated per year (instead of 24 in the study). CONCLUSION: Aside from staff, imaging and dosimetry, the current hospital reimbursements largely underestimated the cost of innovation related to equipment and sources.

Dry anaerobic digestion in batch mode: design and operation of a laboratory-scale, completely mixed reactor.

A laboratory-scale (40 l) reactor was designed to investigate dry anaerobic digestion. The reactor is equipped with an intermittent paddle mixer, enabling complete mixing in the reactor. Three consecutive batch dry digestion tests of municipal solid waste were performed under mesophilic conditions and compared to operation results obtained on a pilot-scale (21 m(3)) with the same feedstock. Biogas and methane production at the end of the tests were similar (around 200 m(3) CH(4)STP/tVS), and the dynamics of methane production and VFA accumulation concurred. However, the maximal levels of VFA transitory accumulation varied between reactors and between runs in a same reactor. Ammonia levels were similar in both reactors. These results show that the new reactor accurately imitates the conditions found in larger ones. Adaptation of micro-organisms to the waste and operating conditions was also pointed out along the consecutive batches.

[The cost of respiration-gated radiotherapy in the framework of a clinical research programme "STIC"]. / Evaluation du coût de la radiothérapie asservie à la respiration dans le cadre d'un projet Stic.

PURPOSE: Our study aims to evaluate the impact of the implementation of respiratory gating (RG) on the production cost of radiotherapy, as compared to conformational radiotherapy without RG (comparator) in patients with lung or breast cancers. Issues surrounding reimbursement were also explored. MATERIALS AND METHODS: A prospective, multicenter, non-randomised study was conducted in the framework of a project entitled "Support Program for Costly Diagnostic and Therapeutic Innovations". Of the 20 hospitals involved in the clinical study, eight reference centers participated to the medico-economic study evaluating the costs of staff and equipment, as well as the costs of maintenance and consumables. RESULTS: Three hundred and sixty-five patients were enrolled over two years in the economic study, corresponding to 197 radiotherapy treatments without RG and 168 with RG. Patients treated during the learning phase (n=27) were excluded from the comparison with the control group. The use of RG in routine practice induced a cost increase of respectively euro1256 and euro996 per treatment for lung and breast cancer patients treated with breath-hold techniques, versus euro1807 and euro1510 for lung and breast cancer patients treated with synchronized gating techniques. Overcosts were mainly due to extra working time of medical staff and medical technicians and to extra use of equipment during treatment sessions. CONCLUSION: The results of the full cost estimation suggested that medical reimbursements largely underestimate the costs related to innovation.

[Impact of FDG-PET on radiation therapy: economic results of a STIC study]. / L'apport de la tomographie par émission de positons au FDG pour la radiothérapie: résultats de l'évaluation économique du Stic "TEP et radiothérapie".

The aim of this study is to assess the effects of Positron Emission Tomography (PET) associated with computed tomography (CT) on resource allocation (costs and savings) of the following treatment in radiotherapy for non small cell lung cancers (NSCLC) and Hodgkin's diseases. A national prospective study was conducted in nine hospitals. Two treatment decisions made on the basis of CT only or on PET associated with, were compared in a before-after design. The direct medical cost of using PET was assessed by micro-costing. The costs of new exams and the costs and savings associated with changes in the chosen treatment were calculated on the basis of reimbursement rates. The economic study was conducted over 2 years and included 209 patients (97 patients with Hodgkin's disease and 112 with NSCLC). The mean cost of using PET, corresponding to an extra cost, was approximately 800 euro (50% for the radionuclide FDG). Radiotherapy treatments were modified for only 10% of patients with Hodgkin's disease with a minor impact on treatment costs versus 40% of patients with lung cancer with a reduction in mean treatment cost of more than 500 euro.

High-solids anaerobic digestion: comparison of three pilot scales.

Two experiments were undertaken in three different experimental set-ups in order to compare them: an industrial 21-m3 pilot reactor, a new 40-l laboratory pilot reactor and bmp type plasma bottles. Three consecutive batch dry digestion tests of municipal solid waste were performed under mesophilic conditions with the same feedstock in all vessels. Biogas and methane production at the end of the tests were similar (around 200 m3 CH4STP/tVS) for both pilot reactors and were different from the bottle tests. The dynamics of methane production and VFA accumulation concurred. However, the maximal levels of VFA transitory accumulation varied between reactors and between runs in a same reactor. Ammonia levels were similar in both reactors. These results show that the new reactor accurately imitates the conditions found in the larger one. Adaptation of microorganisms to the waste and operating conditions was also pointed out along the consecutive batches. Thermophilic semi-continuous tests were performed in both reactors with similar conditions. The methane production efficiencies were similar.

[Patients' preferences and decision-making: state of the art and applications in cancer]. / Préférences des patients et prise de décision : état des lieux et retour d'expérience en cancérologie.

BACKGROUND: This paper deals with the physician-patient encounter. In France, the current legal framework allows patients to be informed (patients' rights to health information) and to participate to decisions regarding their own health. In such a context, this paper aims to give the reader the broad key components of the so-called 'patient treatment preferences elicitation process' in breast cancer, our research area. METHODS AND RESULTS: We first present the general context, with a definition of the different physician-patient models. We then present decision aids, tools that aim to provide high-quality information to patients in the decision-making process. Finally, based on our previous studies and on examples drawn from the international literature, we present the empirical process of patients' preferences elicitation, which not only increases patients' knowledge of and satisfaction with the decision made, but also allows patients to be part of their disease management. CONCLUSION: Far from being a phenomenon in the air supported by a legal system, this method developed in the 90s allows patients and more generally healthcare users to be autonomous without constraining them to a choice.

[Preliminary results of the assessment of intensity modulated radiotherapy (IMRT) for prostatic and head and neck tumors (STIC 2001)]. / Résultats préliminaires de l'évaluation de la radiothérapie conformationnelle avec modulation d'intensité (RCMI) pour le traitement des cancers prostatiques et ORL (STIC 2001).

INTRODUCTION: Between May 2002 and May 2004, eight French comprehensive cancer centres did a prospective nonrandomized study including 200 patients, 100 with cancer of the prostate and 100 with head and neck cancers. Half of each patient group was treated by IMRT and the others by RTC 3D. This clinical study was associated with an economic study and a physics study. We report here the first results. PATIENTS AND METHODS: For the clinical study, the analysis of the data of the first 88 patients irradiated for a prostatic cancer shows that 39 received RTC and 49 IMRT with a mean dose of 78 Gy at the ICRU point at 2 Gy per fraction. For H&N tumours, the preliminary analysis was done on the 87 first patients with a mean follow-up of 11.5 months (2 to 25 months) and a median of 8.4 months for the IMRT groups and 13.2 months for the RTC group. The economic study was done on the first 157 patients included during the first 18 months: 71 treated by RTC (35 for H&N and 36 for prostate) and 86 treated by IMRT (38 for H&N and 48 for prostate). The assessment of the direct costs was realized by a micro-costing technique. The physical study compared dose distributions for both techniques and has created quality control recommendations. RESULTS: Clinical studies of the acute reactions do not show any difference between groups, but we want to point out the short follow-up and the relatively high dose delivered to cancers of the prostate. The physics study demonstrates that IMRT is technically feasible in good clinical conditions with high quality assurance, a good reproducibility and precision. Dosimetric data show that IMRT could certainly spare organs at risk more than RTC for H&N tumours. The direct costs of "routine" treatments for H&N tumours were 4922 euros for IMRT versus 1899 euros for RTC and for the prostatic cancers 4911 euros for IMRT versus 2357 for RTC.

[Intensity modulated radiotherapy (IMRT) in France: The boost of the national funding for the new expensive innovative technologies (STIC 2001 and 2002)]. / La radiothérapie conformationnelle avec modulation d'intensité (RCMI) en France: apport des projets nationaux de soutien aux technologies innovantes et coûteuses (STIC 2001 et 2002).

The STIC 2001 and STIC 2002 projects intend to allow the implementation and the assessment of Intensity Modulated Radiation Therapy in France. IMRT is an innovative technique in which the high-dose radiation volume conforms to an accurately defined target volume with less morbidity to the surrounding normal tissues. The main medical objectives of the projects are (1) to improve the therapeutic index while decreasing acute toxicity and late sequelae (mainly xerostomia and acute mucite for head and neck tumors), which allows an increase in the radiation dose to the tumor and then a better tumor control; (2) to propose a salvage treatment to patients who locally recurred in previously irradiated sites; (3) to determine the optimal treatment guidelines for a safe use of the technique in clinical routine. Our projects also aim at comparing IMRT and 3D conformal treatments on the one hand (STIC 2001), and IMRT and conventional treatments on the other hand (STIC 2002), with regard to costs. As a matter of fact, the use of IMRT is presently limited in France because its implementation requires high investment and personnel costs. The seventeen French Regional Cancer Centres involved in the two projects intend to study the additional cost of the use IMRT in comparison with the use of standard techniques, which appears to be a step for a wide use of this technique in France. Each of the studies is two-year prospective, and includes patients with head and neck tumors treated with a curative intend (post operative or exclusive treatments for STIC 2002 and STIC 2002), and patients with a prostate cancer (STIC 2001).

[Cost-effectiveness in diagnosis and treatment of carcinomas of unknown primary origin]. / Analyse Coût/efficacité de la prise en charge diagnostique et thérapeutique des carcinomes d'origine indéterminée.

The aim was to compare, in terms of cost-effectiveness, two diagnostic strategies for finding out the primary site of tumors revealed by metastasis, adopting the hospital's perspective. The observed strategy reflected the usual practices of doctors at the Regional Cancer Center in Toulouse (France), and was based on a sample of 202 patients of this Center. The standardized strategy, which reflected limited diagnostic investigation, was simulated using the same sample of patients to whom we applied the recommendations of local experts. In the low assumption regarding the effectiveness of the standardized strategy, the observed strategy compared to the standardized one raised the life expectancy from 407 to 418 days at an incremental cost of $US 1,236 per patient (1996 values). In this case, one day of additional life induced a cost of $US 112 per patient. In the high assumption, the incremental effectiveness was null and the incremental cost was $US 1,236 per patient. In conclusion, the effectiveness of the observed strategy as compared to the standardized strategy was highly questionable, given that the patients' quality of life was not taken into account.

[How to evaluate the quality of information transfer from physician to patient? Choice of psychometric tests for a decision tree in a Regional Cancer Centre]. / Comment évaluer la qualité du transfert de l'information du médecin au patient? Le choix des tests psychométriques d'un tableau de décision dans un Centre Régional de Lutte contre le Cancer.

BACKGROUND: Decision boards are used to transfer information from physicians to patients to help them participate in the clinical decision-making process. We present the tests and results of the psychometric properties of a decision board in a sample of healthy volunteers. METHODS: In the Regional Cancer Centre located in Lyon, we developed a decision board for post-menopausal women with breast cancer after lumpectomy without any poor prognostic factors. Two treatment options were proposed, one involving chemotherapy and the other not. We tested for the following psychometric properties: comprehension, construct validity and reliability. Comprehension was evaluated using a questionnaire, in order to test whether the rates of correct answers were due to chance alone. The construct validity was assessed by changing the information provided (relapse and survival rates, characteristics of chemotherapy) and testing whether the proportion of healthy volunteers choosing an option changed in a predictable and significant way. The reliability was evaluated using the test-retest method. Two reliability statistics were computed: the Pearson correlation and the Intraclass Correlation Coefficient. RESULTS: In the sample of 40 healthy volunteers, 23 chose the option with chemotherapy and 17 the option without chemotherapy. Results show that the decision board was comprehensive, valid (the women changed their choices in a predictable way) and reliable (Pearson correlation and Intraclass Correlation Coefficient close to 1). CONCLUSION: The choice of the psychometrics properties tested and the statistical tests used are discussed. The psychometric properties of our tool are found to be satisfactory.

Shared decision-making in question.

Over recent years, communication within the physician-patient relationship has been profoundly changing. New modes of conveying diagnostic and therapeutic information influence the way in which decisions regarding treatment are made. We propose a critical review of the various theoretical models as presented in the literature, from the paternalistic to the shared decision model, in order to reveal conceptual ambiguities and their related methodological problems. This analysis leads to a project for clarifying these problems through a research protocol based on shared decision-making.

[Effects of the preparation on anxiety before bronchoscopy]. / Effets de la préparation sur l'anxiété avant la fibroscopie bronchique.

In their daily practice, the nurses note the patients' anxiety when they are in hospital for diagnosis exams. Considering this observation, we wanted to assess the potential benefits provided by the behavioural and relational techniques, such as sophrology, maintenance of the help relation, visualization-relaxation. In order to carry out this survey, we adopted the model of Betty NEUMAN, who relies on the concept of homeostasis and on the stress theory of Hans Seyle. The measurement of anxiety by the STAI (State Trait Anxiety Inventory), a scale worked out by SPIELBERGER, enabled us to prove that these relational tools, used by the nurses, made it possible for the patients to better mobilize their adjustment or coping strategies. Recommendations concerning the management of anxiety were set out as not to trigger an attitude of vigilant coping.

Economic impact of harmonizing medical practices: compliance with clinical practice guidelines in the follow-up of breast cancer in a French Comprehensive Cancer Center.

PURPOSE: The introduction of clinical practice guidelines (CPGs) and the increasing desire to harmonize clinical practices draw attention to the economic impact of these trends. In 1994, CPGs were introduced in a French Comprehensive Cancer Center (Centre Régional Léon Bérard, Lyon). We evaluated the application of these CPGs in addition to the consequences of harmonizing clinical practices with respect to the distribution of resources by specifically analyzing the posttherapeutic follow-up of patients with localized breast cancer. METHODS: A before-and-after analysis of the records of patients who received posttherapeutic follow-up for localized breast cancer as of either 1993 or 1995 was performed. Two hundred records were chosen at random, 100 from 1993 and 100 from 1995. Follow-up was continued for as long as possible and CPG compliance was studied for each year of the follow-up periods. RESULTS: Follow-up that was not CPG-compliant required a significantly greater amount of resources. This difference was due to neither consultations nor mammographies, but was due to other examinations that were systematically performed without any warning signs to justify them. Depending on the follow-up year, noncompliant follow-up cost the Social Security from 2.2 to 3.6 times more than compliant follow-up. A noticeable change in medical practices was observed after the introduction of CPGs in 1994. This was confirmed by a sharp decrease in mean Social Security expenditure per patient of more than one third between 1993 and 1995, regardless of the follow-up year considered. CONCLUSION: In the follow-up of patients with localized breast cancer, a large decrease in costs has been observed along with the evolution of medical practices toward CPG compliance. This finding is probably generalizable to other settings, but there is nothing that proves that it is applicable to other treatment strategies.

Analysis of the eligibility of published economic evaluations for transfer to a given health care system. Methodological approach and application to the French health care system.

CONTEXT: Economic evaluations are costly and cannot always be carried out locally. Therefore, decision-makers may wish to use studies already performed in other settings. OBJECTIVE: To define a method for assessing the eligibility of published economic evaluations for transfer to a given health care system and apply it to the french health care system in the clinical situation of adjuvant therapy for women with breast cancer. METHODS: (1) Literature search in six databases from 1982 to 1996; (2) critical appraisal of articles based on four inclusion criteria; and (3) assessment of the eligibility of the studies for transfer based on five indicators. RESULTS: We identified 26 published economic evaluations concerning adjuvant therapy in women with breast cancer. Six (23%) met all four criteria used to select studies, but none of these studies were eligible for transfer to the french health care system. The main reason was that cost data was not reported in a transparent way. CONCLUSIONS: To improve the transferability of economic evaluations, we recommend that requirements for data provision in publications be standardized and international collaboration strengthened.

[Integration of economic criteria in the recommendations for clinical practice in cancerology]. / Intégration des critères économiques dans les recommandations pour la pratique clinique en cancérologie.

Clinical practice guidelines have been defined as "systematically developed statements to assist practitioners and patients in their decisions about appropriate health care for specific clinical circumstances". Their objectives are to improve the quality of health care and to optimise the use of limited health care resources. However reduction of unnecessary costs of delivered health care is proceed most often in an implicit way by identifying inappropriate health care strategies. The increase of health care costs needs to look at this issue in a more explicit way and to consider costs in the guideline development process. The key objective of our study is to analyse the methodological aspects of dealing with cost issues in the guideline development process. The integration of cost issues is in fact limited by two major problems: first, the lack of economic evaluation for many strategies in the scientific literature and second, the lack of generalizability of the published results to temporally and/or geographically different settings. These difficulties are likely to result in the need for local cost evaluation (for a given setting), and though to make the guideline development process much more complex. Further methodological research is important to define the role of economic evaluation in clinical practice guidelines and to enable the integration of cost issues into the guideline development process. They should go closely together with international standardisation of the methodology for designing, conducting and reporting economic evaluation.

Is Helicobacter pylori eradication a cost-effective treatment of duodenal ulcer disease?

Treatment strategies aimed at eradicating Helicobacter pylori have shown positive results in the management of duodenal ulcer disease. Several cost-effectiveness studies comparing these regimens with traditional therapy have recently been conducted, and results are discussed in this review. Cost comparisons of different treatment strategies cannot be performed without first identifying whether the cost of ulcer diagnosis is included in the study. Assuming that only 20% of patients with dyspepsia actually have ulcer disease, costs may vary, depending on the study population. Importantly, treatment costs should not be compared between a patient population with confirmed ulcer disease and one without confirmed disease. In patients with confirmed ulcer disease, studies consistently show that H. pylori eradication strategies are associated with greater efficacy and lower costs than traditional treatment, and are therefore a more cost-effective alternative to standard therapy. Although all models used in the cost-effectiveness analyses assume that patients discontinue treatment following successful eradication of the microorganism, in clinical practice some patients continue antisecretory treatment beyond this period. Thus, savings as a result of H. pylori eradication may be less substantial than indicated in cost-effectiveness studies.